article · Biomolecules & Therapeutics
Researchers have developed novel peptide fusion inhibitors targeting the heptad repeat domains of the SARS-CoV-2 spike protein to block viral entry. Twelve candidate peptides were created, consisting of a short 24-mer peptide, a longer 36-mer peptide designated peptide #2, and ten structural analogues of peptide #2. Unlike the original SARS-CoV, cell-to-cell fusion driven by the SARS-CoV-2 spike protein was not blocked by the shorter 24-mer peptide. In contrast, peptide #2 demonstrated strong fusion inhibition at a concentration of 1 micromolar, alongside three analogues displaying half-maximal inhibitory concentrations between 4.7 and 9.8 micromolar. In pseudovirus testing, peptide #2 inhibited infection at a half-maximal inhibitory concentration of 1.49 micromolar. Showing effective viral suppression without cellular toxicity, these peptide candidates provide leads for the design of prospective antiviral therapeutics and preventatives.
Identifying new ways to stop coronaviruses from entering human cells is essential for building resilient defences against pandemic threats. By demonstrating that specific peptide sequences can disrupt viral fusion without damaging host cells, this work identifies molecular targets and lead molecules that could assist in developing targeted treatments or preventive drugs to counter SARS-CoV-2 infection.
This research is at an early experimental stage, focusing on laboratory design and in vitro assays. The findings could serve pharmaceutical and biotechnology companies seeking lead molecules for antiviral drug discovery programmes. If further developed, these safe and active peptide fusion inhibitors could eventually lead to prophylactic interventions or therapeutic medications designed to manage SARS-CoV-2 and related viral infections.
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A novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), caused a worldwide pandemic. Our aim in this study is to produce new fusion inhibitors against SARS-CoV-2, which can be the basis for developing new antiviral drugs. The fusion core comprising the heptad repeat domains (HR1 and HR2) of SARS-CoV-2 spike (S) were used to design the peptides. A total of twelve peptides were generated, comprising a short or truncated 24-mer (peptide #1), a long 36-mer peptide (peptide #2), and ten peptide #2 analogs. In contrast to SARS-CoV, SARS-CoV-2 S-mediated cell-cell fusion cannot be inhibited with a minimal length, 24-mer peptide. Peptide #2 demonstrated potent inhibition of SARS-CoV-2 S-mediated cell-cell fusion at 1 µM concentration. Three peptide #2 analogs showed IC50 values in the low micromolar range (4.7-9.8 µM). Peptide #2 inhibited the SARS-CoV-2 pseudovirus assay at IC50=1.49 µM. Given their potent inhibition of viral activity and safety and lack of cytotoxicity, these peptides provide an attractive avenue for the development of new prophylactic and therapeutic agents against SARS-CoV-2.
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DOI: 10.4062/biomolther.2020.201
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